title: Artesunate in combination with oxacillin protect sepsis model mice challenged with lethal live methicillin-resistant Staphylococcus aureus (MRSA) via its inhibition on proinflammatory cytokines release and enhancement on antibacterial activity of oxacillin.
abstract: Sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) has worse outcome because of multiresistance to a large group of antibiotics, which may lead to death from septic shock. In the present study, we firstly found that artesunate in combination with oxacillin was capable of protecting mice challenged with live MRSA WHO-2 (WHO-2) and the protection was related to the reduced TNF-α and IL-6 levels and decreased bacterial load. Based on above results, artesunate was further investigated from two aspects in vitro, anti-inflammation effect and antibacterial enhancement effect on antibiotics. Artesunate not only inhibited TNF-α and IL-6 release but also inhibited mRNA and protein expressions of TLR2 and Nod2, two important receptors, in murine peritoneal macrophages stimulated with heat-killed WHO-2, further demonstrating anti-inflammatory effect of artesunate was related to the inhibition of TLR2- and Nod2-mediated proinflammatory cytokines. Significantly, artesunate enhanced antibacterial activity of oxacillin and ampicillin not levofloxacin against WHO-2 and a clinical MRSA strain; the fractional inhibitory concentration indexes were lower than 0.5. Further, artesunate possessed moderate affinity for penicillin-binding protein 2a (PBP2a) and reduced the mecA mRNA expression up-regulated by oxacillin, suggesting that artesunate's enhancement on antibacterial activity of β-lactams was related to the inhibition of PBP2a and down-regulation of mecA mRNA expression. In conclusion, our results demonstrated that artesunate in combination with oxacillin protected mice challenged with lethal live MRSA via its inhibition on proinflammatory cytokines release and enhancement on antibacterial activity of oxacillin. Artesunate could be further investigated as a candidate drug for MRSA sepsis.
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Jiang
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Xinchuan
authors.initials: X
authors.lastname: Zheng
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Cen
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Xichun
authors.initials: X
authors.lastname: Pan
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cao
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000235:genetics; D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D058491:Bacterial Load / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D053473:Nod2 Signaling Adaptor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010068:Oxacillin / Q000494:pharmacology*; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors; D018805:Sepsis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000382:microbiology*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000241:Adenosine; D000667:Ampicillin; D000900:Anti-Bacterial Agents; D015703:Antigens, CD; D037621:Artemisinins; D000077332:Artesunate; D016207:Cytokines; D015850:Interleukin-6; D053473:Nod2 Signaling Adaptor Protein; D010068:Oxacillin; D046915:Penicillin-Binding Proteins; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D047090:beta-Lactams; D000093242:Interleukin-6 Inhibitors; C495945:Nod2 protein, mouse; C493486:Tlr2 protein, mouse; C046756:5'-N-methylcarboxamideadenosine